By Kirsten Malenke
July 18, 2016
Researchers identify a major reason why the protein alpha-synuclein is toxic to neurons in the brain
Researchers at the University of Pittsburgh School of Medicine have discovered a major reason why the protein alpha-synuclein - a major component of the Lewy bodies that are the pathological trademark of Parkinson's disease - is toxic to neurons in the brain. These findings, published in Science Translational Medicine, may potentially lead to new therapies that could slow or halt the progression of the disease.
Parkinson's disease (PD) is a degenerative neurological disease that causes tremors, slowness and difficulties with gait and balance. The symptoms are caused by the degeneration and loss of neurons in the brain, especially those vital for the initiation and coordination of movement. According to the American Parkinson's Disease Association (APDA), Parkinson's disease affects about one million people in the United States.
Lead study investigator J. Timothy Greenamyre, MD, PhD, Love Family professor of neurology in Pitt's School of Medicine and director of the Pittsburgh Institute for Neurodegenerative Diseases (PIND), is also director of the APDA Advanced Center for Parkinson's Disease Research at PIND and a member of the APDA Scientific Advisory Board. "It's really exciting that we have found a mechanism we can target to create new treatments for this devastating disease," Greenamyre said. "I've been involved in Parkinson's research for more than 25 years and the further I go along, the more urgency I feel to translate what we're doing in the laboratory into something that's going to make a meaningful difference for people affected by Parkinson's disease. I believe these findings will have a lot of impact in the Parkinson's research community."
Prior Knowledge
Prior to this study, researchers knew that degenerating neurons contain large bundles of a protein called alpha-synuclein, which plays a key role in the development of the disease. Individuals whose cells make a mutated form of alpha-synuclein develop a particularly aggressive form of PD, while people whose cells make too much alpha-synuclein have a higher risk of developing Parkinson's due to the protein's toxicity.
In addition to this, researchers knew that, if a cell produces too much alpha-synuclein, mitochondria in the cell do not function properly. Mitochondria are best known for their role in producing the energy that all cellular processes require. In neurons, more than 90% of the energy is supplied by mitochondria. Because they also produce and detoxify free radicals, mitochondria can cause oxidative damage if they're not functioning properly.
Findings
In this study, Greenamyre and his colleagues used rodent models of PD to pinpoint exactly how alpha-synuclein impedes efficient mitochondrial function. They found that specific forms of alpha-synuclein stick to a receptor on the surface of the mitochondria called TOM20, which typically recognizes proteins that need to be imported into the mitochondria.
"Normally these proteins are imported, function, get damaged and then get replaced-it's an ongoing process," Greenamyre explained to ADVANCE. The components of the mitochondria need to be constantly replenished, but when alpha-synuclein binds to TOM20, it blocks that process, preventing needed proteins from being imported into the mitochondria.
This results in inefficient mitochondria that can't replenish themselves and subsequently produce less energy and more damaging cellular waste, ultimately causing neurodegeneration. Greenamyre analogized, "The effects of alpha-synuclein on mitochondria are like making a perfectly good coal-fueled power plant extremely inefficient, so it not only fails to make enough electricity, but also creates too much toxic pollution." The researchers then confirmed their animal findings in post-mortem brain tissue from people with PD.
By using cell cultures, researchers also identified two ways gene therapy could protect neurons from toxic alpha-synuclein. One way would force the neurons to make more TOM20 protein than normal to essentially "sop up" the toxic synuclein, allowing the mitochondria to function properly. Researchers also found that forcing neurons to produce a protein called MTS kept alpha-synuclein from binding to TOM20, which prevented alpha-synuclein's adverse effects on mitochondria.
Impact
"I think the real impact is that we defined a specific way in which alpha-synuclein is interacting with and disabling the mitochondria, and it's only by defining these molecular mechanisms that you can design specific treatments to try and prevent that from happening," said Greenamyre. "We're looking at gene therapy, but there are other approaches that might take off from these results - so I think that the real importance is basically coming up with new ways that you might be able to intervene therapeutically to slow down or stop the disease progression."
"This is an important study," said David G. Standaert, MD, PhD, chair of the APDA Scientific Advisory Board, John N. Whitaker professor and chair of Neurology, and director of the division of movement disorders at the University of Alabama at Birmingham in a June 8 APDA press release. "It provides new insight into two of the critical mechanisms in Parkinson's disease: aggregation of the protein alpha-synuclein and dysfunction of mitochondria, the 'powerhouse' of neurons. It opens doors to new kinds of treatments to slow or prevent the disease."2
Future Research
Further research is necessary to determine if these methods could help people with PD, though Greenamyre is hopeful that one or both may eventually make it into human clinical trials in an effort to slow or stop the disease's otherwise unavoidable progression. "These protective gene therapy studies in rats are just beginning in the lab right now; we don't have any results yet but we're very excited about trying to cure Parkinson's disease in the rats as a first step towards taking this into human trials," said Greenamyre. "There are many lines of research going on right now with this and we're very excited about it."
Kirsten Malenke is a staff writer at ADVANCE. Contact: kmalenke@advanceweb.com
References:
1. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Science Translational Medicine. http://stm.sciencemag.org/content/8/342/342ra78
2. American Parkinson's Disease Association. University of Pittsburgh Researchers Find Key to Parkinson's Disease Neurodegeneration. http://www.apdaparkinson.org/press-release-06-08-16/
No comments:
Post a Comment